Survivin is a member of the IAP (Inhibitor of Apoptosis) family of proteins, and is highly expressed in all primary tumor types. Survivin is undetectable in most normal differentiated tissues, but is present in normal placenta, testes, and rapidly dividing cells such as CD34+ bone marrow stem cells. High expression of survivin in tumors is correlated with poor survival among patients with non-small cell lung cancer (NSCLC) [Ref. 1]. Suppression of survivin induces tumor cell death and renders the cells sensitive to normal cell cycle regulation [Ref. 2-Ref. 4]. Given its preferential expression in tumor cells, its ability to block apoptosis and regulate cancer cell proliferation, and its correlation with poor survival, survivin stands out as a putative novel target for cancer therapy. It has been reported that the down-regulation of survivin expression by the antisense or siRNA of survivin was shown to sensitize tumor cells to various anticancer drugs [Ref. 7-Ref. 13].
Fused condensed imidazolium derivatives which are expected to be candidates for anti-tumor agents having good anti-tumor activity, low toxicity and wide broad safety margins are disclosed in International Publications [Ref. 5 and Ref. 6]. Particularly, 1-(2-methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium bromide (hereinafter YM155), shown by the following formula, is a compound which is expected to be useful as an anti-tumor agent, because it has good in vivo tumor growth inhibitory activity and low toxicity.

YM155 is the first compound found to specifically suppress survivin and it has potent anti-tumor activities in experimental human hormone refractory prostate cancer (HRPC) xenograft models [Ref. 14], human NSCLC xenograft models [Ref. 15], and in patients with advanced solid tumors and non-Hodgkin's lymphoma (NHL) [Ref. 16 and Ref. 17]. YM155 showed time-dependent anti-tumor activity, and 7-day continuous infusion of YM155 induced tumor regression in the NSCLC xenograft model [Ref. 15]. YM155 caused fewer side effects, e.g., body weight decrease and hematological toxicities which are frequently observed with paclitaxel, cisplatin and doxorubicin treatment [Ref. 16 and Ref. 17].
In general, there is a limit to efficacy of chemotherapy for tumors, particularly malignant tumors, when an anticancer agent is administered alone, in view of adverse reactions, and it is quite rare to attain a sufficient anticancer effect. In a clinical practice, accordingly, a multi-drug combination therapy in which 2 or more species of drugs having different mechanisms of action are used in combination has been employed. Through combination therapy, reduction of adverse drug reaction and potentiation of the anticancer activity are intended by combination of anticancer agents having different mechanisms of action, including 1) reduction of the non-sensitive cell population, 2) prevention or delaying of occurrence of drug resistance, and 3) dispersing of toxicity by means of a combination of drugs having different toxicities. With combination therapy, however, a random combination of anticancer agents having different mechanisms of action does not necessarily yield a potentiation effect of anticancer activities. Thus, studies have been conducted to obtain a combination of anticancer agents having a much higher anticancer action.
Representative combinational drugs include, for example, cisplatin and gemcitabine as well as carboplatin and paclitaxel, which are known as standard combination therapy for lung cancer [Ref. 18 and Ref. 19]. A randomized phase III study of combination therapies, R-ICE (rituximab, ifosfamide, carboplatin and etoposide) and R-DHAP (rituximab, cisplatin, Cytarabine (ara-C) and dexamethasone) is in progress in patients with lymphoma (DLBCL) [Ref. 20, 21 and 22].
When the combinational drugs are used together, there are a lot of cases where the side effects increase as well as the anti-tumor effects. Therefore there are many difficulties in combining two or more anti-tumor agents. Especially, a combination of anticancer agents with a synergistic anticancer action resulting in marked reduction of cancer cells and further complete removal of the cancer cells, leading to a complete cure of cancer without an increase of side effects, is eagerly desired.